Halogenation of steroids



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Patented Jan. 12, 1954 UNITED STATES OFFICE! Michigan No Drawing. Application1 0ctober'1v5,` "1951;

Serialr-No. 25191511" 15 claims. (C1. 26o-397.4)

'Ihefpresent` invention relatestoa novel Vprocess for-'thepreparationnof certain steroid compounds andzis more particularly concernedl with a process forftheproduction of 4-halo-2l#acyloxy-l'la-hydroxypregnane3,l1,20ltrionesby the halogenaftion of f 2leacyloxye17a-hydroxypregnane-3,11,20- triones. 1

It is an object of-the present invention to providea novel process fior the `halogenation of A21-` acyloXy-'lTahydroxypregnane;1,20-triones to produce 4-halo-21-acyloxy-l'laLhydroxypregnane3,1f1,20#triones. Other objects of the inventionwill be apparent to those skilled in the art toz which 'this invention pertains.

According to the present invention, a 21-acyl- Oxy-17lhydroxypregnane3,l-1,2Q#trione is reacted with-a halogenating agent in tertiary `butyl alcohol toproduce-halogenation at carbon atom four of thesteroidnucleus.`

Startingcompounds yfor .the methodromhe present invention. are:-21-acyloxy-17a-hydroxypregnante-3,11,20-triones, especially such compounds -swherein theV ,21:facyloxy. group 1 contains fromzconevtooeght carbon atoms; such acyloxy; groups including, forexampla iormoxy; Vacetoxy, propionoxy,` ,butanoy1oxy,- isobutanoyloxyr valer;- oyloxy, isovaleroyloxy, hexanoyloxy;:heptanoyle` oxy, voctanoyloxy,isooctanoyloxm and the like, and these acyl groups mayl carry non-reactive substituents, such as halo; alkoxy; alkyl, and the likepif i desired.

The starting` 2lfacyloxy:17ehydroxypregnane-` alsl-triones are l prepared by. oxidation. of 21- acelerar,3,17-diloydroxrlpregnanef1nzoqdiones,` by: conventional produreysuch aschromic acid oxidation. These compounds are in turn preparertlo'y'-l replacement ofthe 2lf'bromine .atom :in 2l-bromo3,17-dihydroxypregnaneflLzO diones, using a selected Organic` acidsodium saltor by Qylatdnf thecorresponding 2,1;hydroxy compound; ,v

Themalo'geuatine agents rused in. the process: of the' presentinvention are agents ca palole'of` causing halogenatio'n at the four position of the' steroid nucleus-,such as, for example; bromine;

chlorine; N-bromoacetamide; N-'chlorosuccin-f irnide,4 'N-brornosuccinimide,` 3-brorno5,5di' methyl'hydantoin, 1,3-dibromo-dimethylhydantoin," hypobromous A acidv and hypochlorous acid. These reagents have all been vfoundto possess thercapacity ofl ellecting `halogenation of the four positionl ofthe-nucleus of :the starting-mw` terial.- For the'r accomplishmentyof such result.4

andwattainmentof ithe highest yie1dsat least the theoretical amount of halogenating agent should be emDlOyed. When the agent contains a single bromine or chlorine atom, thetheoretical proportion is two molesof afgenttfofonemole of starting steroid, b ujt when twohalogen atoms are present in ther-halogenationagent,` only one mole of agent per *mole of steroid- 'is "theoretically required. Ordinarily',A it is preferred touse an excess of the halogenating reagent over the theoretical amount, e. g., from oneto vemoles of agent per mole of steroid. Although' less than the theoretical proportion maybe used if desired, it should be obvioustha-t lower yields and conversions are obtained by such manner.

In carrying out theplocess Aof the present invention; one4 molar part of thestarting 21-acyloxy-l7afhydroxypregnane;3,11204trione is ad: mixed, usingeither order of addition,with at least thetheoretcal.amountiof halogenating agent in tertiary vbutyl; lalcohol nat` a temperature i below aboutftydegrees centigrade, preferably between about iifteerr and about forty degrees centigrade. Pyridine and; other 'acid-binding solvents should notibetcmployed"as` solvents, nor should substantial amounts'of acidfoinding reagents such as pcvitassiurrracetate.` or the like be added to, or be presentin;` the reaction mixture. The length of the reaction time is notcritical, depending some-V what upon the starting materials and reaction conditions z employed, infathis` `respect varying somewhat inverselyrwith the proportions of reactantsand temperatureemployed, and reaction Periodsjof Vonetoten days have been found satisfactory, lfor example, usingroom temperature. At. .the end of the .reaction period, the desired product. may` usually be `separated `from the mix-` ture of reaction products as a crystalline solid, washedwith solvent-and driedI to give the more highly puriedcrystalline material. Additional materialmaybe ,obtained by `adding waterl to the nitrate of the'ireaction mixture.`

The solvent used-in the method ofthe invention is tertiaryirbutyl alcohol. i It `hasloeen found that in Y :this solvent.r the-` products, 4-halo-21- acyloX-y-l'liuY `hydroxypregna-ne" 3,11g201 triones, crystallize' 1 outi. in a high state;` of ypurity. This result is very important, especially in the case of thee-brame compoundsfsince, inlsolution in the presence of hydrogen-ions, these products readily rearrange or yfurther halogenate to give undesired The .yieldo'f desired reaction product is usually between about forty fand about sixty-ve per cent, buts :by application ofi `optimum i reaction conditionsfdahethigher'ryieldsfcam becobtained consist-` ently. However, conversions of eighty-nrei to ninety-five per cent can be obtained since product of low purity can be regenerated to starting material by treatment with zinc in acetic acid.

The presence of water in amount between about traces and about eighteen per cent of the volume of the solvent is advantageous. With no water present the reaction proceeds sluggishly, while with considerable water present the same result is observed. eighteen per cent of water, preferably about one to above iive per cent of water, the reaction both proceeds at a reasonable rate and gives high yields of desired product. The addition of mineral acid to the reaction mixture is advantageously employed to start the reaction.

The following examples illustrate the method of the present invention, but are not to be construed as limiting.

To 404 milligrams (1.0 millimole) of 21-acetoxy-17a hydr0Xypregnane-3,11,ZO-trione [prepared from 3,17 dihydroxypregnane-lL20-dione ISarett, J. Am. Chem. Soc. 70, 1454 (1948)] by bromination in chloroform to give the 21- bromo derivative followed by reaction with ptassium acetate in reuxing acetone to give 3,17- dihydroxy 21 -aeetoxypregnane-11,20 dione, which is then oxidized in the three position with N-bromoacetamide in basic solution] dissolved in 48 milliliters of tertiary butyl alcohol, was added 0.75 milliliter of water containing 0.122 milliliter of forty-eight per cent aqueous hydrogen bromide (one millimole of hydrogen bromide) and 276 milligrams (two millimoles) of N-bromoacetamide. The mixture was allowed to stand for 49 hours at room temperature whereafter the crystals were filtered off. The filtrate was concentrated under nitrogen to one-half its Volume and allowed to stand overnight. A second crop of crystals was ltered oir, washed with alcohol and dried. The yield was 297 milligrams (61.4 per cent) of 4bromo21-acetoxy-17a-hydroxypregnane 3,1120 trione, melting at 200202 degrees centigrade with decomposition and having an [5.11323 of plus 99 degrees in acetone.

Example 2.--4-b1'omo-21-acetoy-Na-hydroxypregnane-BJ 1 ,Z0-trionfa In the same manner as given in Example 1, 4- bromo 21 acetoxy 17a hydroxypregnane- 3,l1,20trione is prepared from 21acetoxy17a hydroxypregnane-S,11,20-trione using N-bromosuccinimide instead of N-bromoacetamide.

Example 3 4-chloro-21 -acetoxy-I 7 a-hyclromypegnane-.SJ 1 ,Z0-triomf In the same manner as given in Example l, 4- chloro 21 acetoxy 17a hydroxypregnane- 3,ll,20trione is prepared from 21-acetoxy-17ahydroxypregnane 3,1'1,20 trione using N- chlorosuccim'mide instead of N-bromoacetamide. The product has a melting point of 244-245 degrees and has an [alD24 of plus 100 degrees in acetone.

In the same manner as given in Example 1, 4- bromo 21 acetoxy 17a hydroxypregnane- 3,l1,20-trione is prepared from 2l-acetoxy-l7ahydroxypregnane-3,11,20-trione using 3`bromo 5,5-dimethylhydantoin instead of N-bromoacetamide.

However, with about one to about In the same manner as given in Example 1, 4- bromo 21 propionoxy-17a-hydroxypregnane- 3,l1,20trione is prepared from 21-propionoxyl7ahydroxypregnane 3,11,20trione using N- bromoacetamide.

Ercample 6.-4 chloro-21-octanoylorcy-Na-hydroypregnane-SJL20-Mone In the same manner as given in Eample 1, 4- chloro-21octanoyloxy17a hydroxypregnane- 3,11,20trione is prepared from 21octanoyloxy 17a-hydroxypregnane 3,11,20trione using N- chlorosuccinimide instead of N-bromoacetamide.

Example 7.-4-bpomo-21 -acetoy-1 7a-hydrozcypregnane-SJ 1 ,ZO-trione To 404 milligrams (1.0 millimole) of 21-acet- Oxy-17a hydroxypregnane-3,11,20-trione, prepared from 2l acetoxy 3,17-dihydroxypregnane-11,20dione by oxidation according to conventional procedure, dissolved in 48 milliliters of tertiary butyl alcohol was added 0.75 milliliter of water containing 0.122 milliliter of 48 percent aqueous hydrobromic acid (one millimole of hydrogen bromide) and milligrams (one millimole) of bromine. The mixture was allowed to stand for 48 hours at room temperature whereafter the crystals were filtered off. The nltrate was concentrated to one-half its volume and allowed to stand overnight. A second crop of crystals was nltered off, washed with alcohol and dried. The yield was 284 milligrams (58.7 percent) of 4-bromo-2l-acetoxy-17a-hydroxypregnane3,11,20-trione melting at 205-207 degrees centigrade with decomposition and having an [alD23 of plus 100 degrees in acetone.

In the same manner as given in Example 7, 4- chloro 21 acetoxy 17a hydroxypregnane- 3,11,20trione is prepared from 21-acetoxy-17ahydroxypregnane-B,11,20-trione using chlorine instead of bromine.

Example .9.-4-bromo-21-acetoy-Na-hydroypregnaae-3,11,20trione In the same manner as given in Example 7, 4- bromo 21 acetoxy-17a hydroxypregnane- 3,11,20trione is prepared from 21-acetoxy-17ahydroxypregnane-3,11,20-trione using 1,3-dibroino-5,5-dimethylhydantoin instead of bromine.

To 404 milligrams (1.0 millimole) of 21-acetoxy-17a-hydroxypregnane 3,'11,20trione, prepared from 21acetoXy-3,17-dihydroxypregnane- 11,20-dione by oxidation according to conventional procedure, dissolved in 25 milliliters of tertiary butyl alcohol was added 3.5 milliliters of aqueous hypobromous acid containing 194 milligrams (two millimoles) of hypobromous acid. After standing at room temperature for three days, the crystals of 4-bromo-21-acetoxy- 17a-hydroxyp'regnane-3J1,20-trione were iiltered off, washed with twenty percent aqueous alcohol and dried. The product had a melting point at 202 degrees centigrade with decomposition and an [alD25 of plus 100 degrees in acetone.

'SILBMBWBS .v t maghi/- Example? 10. hvdrcx 1st spared i tenerlo relidfhydrerypregnane Lmftrisme using..brnechlerousacidJ instead'vf hypobrsimeus acid.

In the samemarnerfa givenirrExamnles `1 "'lihrqughlll i @63110351517 parent to one skilled in the art, and the inVen-"` tion-isV4 therefore to be limited only bythegscope fof theapper-1ded-claims` Y We" claim:

i l-. A-processMfor thewhalogenationffofa 121- acyloxy-17ahydroxypregnane-3,11,20-trione to produce a 4-halo-21-acyloxy-l'la-hydroxypregnane-3,l1,20trione by reaction therewith of a halogenating agent which consists in mixing such halogenating agent and a 21-acyloxy-17a-hydroxypregnane-3,11,20-trione in tertiary butyl alcohol containing up to about eighteen per cent Water by volume.

2. A process for the halogenation of a 21 acyloxy-17ahydroxypregnane-3,11,20-trione to produce a 4-halo-21-acyloXy-l'7a-hydroxypregnane-3,11,20trione by reaction therewith of a halogenating agent which consists in mixing such halogenating agent and a 21 acyloxy1'7ahy droXypregnane-3,lL20-triche in tertiary butyl alcohol containing up to about eighteen per cent water by volume at a temperature below about fifty degrees centigrade, to cause halogenation at carbon atom four of the steroid nucleus.

3. A process for the halogenation of a 21- acyloxy-lla-hydroxypregnane-B,11,20-trione to produce a 4-halo2l-acyloxy-17a-hydroxypregnane-3,11,20-trione by reaction therewith of ahalogenating agent which consists in mixing such halogenating agent and a 2Vl-acyloxy-17a-hydroxypregnane-3,11,20-trione in tertiary butyl alcohol containing up to about eighteen per cent Water by volume at a temperature below about fifty degrees centigrade. to cause halogenaton at carbon atom four of the steroid nucleus, and separating the 4-halo-21-acyloxy-l'a-hydroxypregnane-3,11,20trione thus produced.

4. A process for the halogenation of a :Z1-acyloxy-17ahydroxypregnane3,1L20-triche to produce a 4-ha1o-2l-acyloxy-17a-hydroxypregnane- 3,11.20trione which comprises: mixing a rearti e with the' corresponding; 214" teaeentsselectedftro hegrpuniconsistineiof N- Nacidaihypoch-lorousvaoid; brominarzandtchlorne.

:ra-.nd a: 2lgacyloxyellagshydroxyprcenanr34h20- v rione:` inttertiary butin;l alcohol containing unito 1;.rabout,.- eighteempen centr :water-by volume, `-ata emperature1belowlaboutifty;deereeseceutierde, 110 to.,cause :ghalogenationf ata.;-caubolfiY atom-fioul? f Gf the steroid nucleus.

5. A process which comprises: mixing,; inran amountfofiataleast:that itheoretcallmreuured t0 .produce rtl1e=,:de-sired'gresulta.` a .ezreagellt-,nseleoted ronrathe.-groupiconsistinefoNfbromoacetamde, s-jfrlechlorosuccinimide, l`tNfbronriisuccinmide, e3- romo-oedimethylh dantoin, .i lfltblOmQ-:- rdimethylhydantoin l. y cida 11m0- chlorousracid;brommerandschlci e and aralcyloxy 417e `ie.:his!drorypl:cana-ne.,

ionegiwheizeinatheacyloxy groupacontains yungto anda-:including eight-.acarbon ratoms. .in ,l rliiely dautylu alcohol :contairline:` rubato.; aboutaeighteen aber cent waterby zvolume'rat. aetemperature abe- 25 tween about fifteen and about forty .degrees :centigrade;f4 tofacause` 1 halogenationgiaty carbon atom-four ofntheA steroidanucleusranchseparating Z1-,the t4-halo2lfacyloxy-L'Iafhydroxypregnanev3,- ilrll,20 rionenthusipprbduced.

1;.;.30 a; csaprocess .whichlcompi-:sesr mixing-'an excess .fr ofi'V Nfbromoacetamide and. a :Zlsacyloxy- Blas-hy- ,oxy group.. containseupoto :andeincluding-fb eight carboni atomsgirn rtertiaryi butylfalcohol lcontainl ine s unzto: abouti eighteen-mer,:centrwater z by-volurne, at a temperature;abelovwrabout:fiiftyrdegrees :,centigrad to-:acause 'bromi-natioir:atccarbomatom miour-roiathe steroid-nucleus; andfseparatingi-ithe f-rdimm-01110121121.@acyloxy@l7aza-hydroxypregnane 40 3,11,20trione thus produced.

'7. A process which comprises: mixing, in a proportion of at least about two moles to one, N- bromoacetamide and 21-acetoxy-1'7a-hydroxypregnane-3,11,20trione in tertiary butyl alcohol containing up to about eighteen per cent water by volume to which a small amount of mineral acid has been added, at a temperature between about fifteen degrees and about forty degrees centigrade, to cause bromination at carbon atom four of the steroid nucleus and separating the 4 bromo 21 acetoxy 17a hydroxypregnane- 3,11,20trione thus produced.

8. A process which comprises: mixing an excess of N-chlorosuccinimide and a 21acyloxy17a hydroxypregnane-3,11,20-trione, wherein the acyloxy group contains up to and including eight carbon atoms, in tertiary butyl alcohol containing up to about eighteen per cent water by v01- ume, at a temperature below about fifty degrees centigrade, to cause chlorination at carbon atom four of the steroid nucleus, and separating the 4- chloro 21 acyloxy 17a hydroxypregnane 3,11,20trione thus produced.

9. A process which comprises: mixing, in a.

proportion of at least about two moles to one, N- chlorosuccinimide and 21-acetoxy-17'a-hydroxypregnane-3,1l,20trione in tertiary butyl alcohol containing up to about eighteen per cent water by Volume to which a small amount of mineral acid has been added, at a temperature between about fteen degrees and about forty degrees centigrade, to cause chlorination at carbon atom iour of the steroid nucleus and separating the 4- chloro 21 acetoxy 17a hydroxypregnane 76 3.11.20-trione thus produced.

10. A process which comprises: mixing an excess of 1,3-dibromo-5,-dimethylhydantoin and a 21-acyloxy-l7ahydroxypregnane-3L29-trione, wherein the acyloxy group contains up to and including eight carbon atoms, in tertiary butyl alcohol containing up to about eighteen per cent water by Volume, at a temperature below about fifty degrees centigrade', to cause bromination at carbon atom four of the steroid nucleus and separating the 4-bromo2lacyloxy l'la-hydroxypregnane-3,l1,2O-trichev thus produced.

11. A process which comprises: mixing, in a proportion of at least about one mole to one, 1,3- dibromo5,5dimethylhydantoin and 21-acetoxy- 17a-hydroxypregnane3,l1,20-trione in tertiary butyl alcohol containing up to about eighteen per cent water by volume to which Ia small amount of mineral acid has been added, at a temperature between about iifteen degrees and about forty degrees centigrade, to cause bromi nation at carbon atom four of the 'steroid nucleus and separating the 4-brorno-21-acetoxyl'la-hydroxypregnane-3,1120 -trione thus produced.

12. A process which comprises: mixing an excess of bromine and a 21-acyloXy-17a-hydroxypregnane-3,11,2()trione` wherein the acyloxy group contains up to and including eight carbon atoms, in tertiary butyl alcohol containing up to about eighteen per cent water by volume, at a temperature below about fifty degrees centigrade to cause bromination at carbon atom four of the steroid nucleus and separating the li-bromo 21 acyloxy 17m hydroxypregnane 3,11,20trione thus produced.

13. A process which comprises: mixing, inra proportion of at least about one mole to one, bromine and 21-acetoxy-l'la-hydroxypregnane- 3,11,20'tri(me` in tertiary butyl alcohol containing up to about eighteen per cent water by volume, to which a small amount of mineral acid has been added, at a temperature between about fteen degrees and about forty degrees centigrade to cause bromination at carbon atom four of the steroid nucleus and separating the 4- bromo 21 acetoxy 17a hydroxypregnane- 3,11,2'0-trione thus produced.

14. A process which comprises: mixing an excess of hypochlorous acid and a 21-acyloxy-17u.- hydroxypregnane-3,11,20-trione in tertiary butyl alcohol containing up to about eighteen per cent water by volume at a temperature below about fifty degrees centigrade, to cause chlorination at carbon atom four of the steroid nucleus and separating the 4-chloro-21-acyloxy-l'Ia-hydroxypregnane-3,11,20trione thus produced.

15. A process which comprises: mixing, in a proportion of at least about two moles to one, hypochlorous Y acid land 21-acetoXy-17a-hydroxypregnane-3,11,20-trione in tertiary butyl alcohol containing up to about eighteen per cent water by volume, at a temperature'between about iifteen and about forty degrees centigrade, to cause chlorination at carbon atomv four of the steroid nucleus and separating the 4-chloro-2lacetoxy-l'a hydroxypregnane 3,11,20 trione thus produced.

Rosenkranz Feb, 5, 1952 

1. A PROCESS FOR THE HALOGENATION OF A 21ACYLOXY-17-A-HYDROXYPREGNANE-3,11,20-TRIONE TO PRODUCE A 4-HALO-21-ACYLOXY-17A-HYDROXYPREGNANE-3,11,20-TRIONE BY REACTION THEREWITH OF A HALOGENATING AGENT WHICH CONSISTS IN MIXING SUCH HALOGENATING AGENT AND A 21-ACYLOXY-17A-HYDROXYPREGNANE-3,11,20-TRIONE IN TERTIARY BUTYL ALCOHOL CONTAINING UP TO ABOUT EIGHTEEN PER CENT WATER BY VOLUME. 